PhD thesis enhanced with ELF collaboration and compounds

News

2018-02-06

On 30 January 2018, Stefan Baumeister defended his dissertation ‘Investigation of the properties of Acyl Protein Thioesterases and their role in Ras depalmitoylation’ at the Max Planck Institute of Molecular Physiology (MPI) in Dortmund. His thesis describes structural determinants for selectivity between two closely related enzymes. Specific inhibitors could be optimized thanks to compounds derived from Dr. Sonja Siever’s ELF programme. The new insights can prove important for understanding the role of these enzymes in the course of cancer.

Baumeister works in Dr Ingrid Vetter’s group, which is dedicated to the determination of the three-dimensional structure of proteins and protein complexes. Access to such information can be pivotal for the success of drug discovery programmes: it enables medicinal chemists to do much more accurate predictions of what modifications will turn a hit compound into a lead and a candidate drug.

In collaboration with Sonja Sievers at the Compound Management and Screening Center (COMAS) also MPI, Baumeister has been investigating APTs (Acyl protein thioesterases). These enzymes can downregulate Ras GTPases, an important family of signalling proteins, which are frequently mutated in cancer. In his PhD studies, Baumeister wanted to find out the major function of APTs and the difference between APT1 and APT2. ‘It is of high interest to dissect the biological roles of APT1 vs. APT2 and identify the protein networks that the two isoforms are involved in and to determine the degree of overlap between these networks. To this end specific inhibitors are highly needed.’

What Baumeister liked about working with ELF is the coming together of scientists with different expertise who work on different topics. ‘The regular telephone conferences with the ELF experts were very rewarding. Hearing them present the results of their medicinal chemistry efforts and discussing different approaches was very stimulating.’ After receiving the compounds, Baumeister used a detergent-free assay he had developed. It was reassuring that the ELF compounds were validated in this assay, as it had been revealed that the presence of detergent may interfere with screening results. In addition, Baumeister managed to obtain co-crystal structures of human APT2 with two of the APT2-specific ELF compounds. At that time point, no such data was available in the public domain.

Further studies on the compounds are planned. A colleague in Sievers’ group is working on in vivo cell studies, and is planning to use the compounds in her research.

Now his PhD is finalized, Baumeister is looking for the next step in his career. He will continue working in the research area, which had his interest since high school. ‘I am very interested to continue working on the development of technologies to solve problems within the drug discovery cycle, probably in the industry.’

The European Lead Factory congratulates Stefan Baumeister with obtaining his PhD degree and wishes him the best of luck in his future career!

Stefan Baumeister’s thesis can be found here. Read about the ELF compounds and co-crystal structures in Chapter 3.3.3, page 73-81.

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The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n' 115489, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7 / 2007-2013) and EFPIA companies' in kind contribution.